3GD3

Crystal structure of a naturally folded murine apoptosis inducing factor

Summary for 3GD3

• Entry DOI: 10.2210/pdb3gd3/pdb
• Related: 1GV4 1M6I 3GD4
• Descriptor: Apoptosis-inducing factor 1, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: alpha and beta protein, acetylation, apoptosis, dna-binding, fad, flavoprotein, mitochondrion, nucleus, oxidoreductase, phosphoprotein, transit peptide
• Biological source: Mus musculus (mouse); More
• Cellular location: Mitochondrion intermembrane space: Q9Z0X1
• Total number of polymer chains: 6
• Total formula weight: 238022.93

Authors

Sevrioukova, I.F. (deposition date: 2009-02-23, release date: 2009-05-19, Last modification date: 2023-09-06)

Primary citation

Sevrioukova, I.F.
Redox-linked conformational dynamics in apoptosis-inducing factor
J.Mol.Biol., 390:924-938, 2009

PubMed Abstract: Apoptosis-inducing factor (AIF) is a bifunctional mitochondrial flavoprotein critical for energy metabolism and induction of caspase-independent apoptosis, whose exact role in normal mitochondria remains unknown. Upon reduction with NADH, AIF undergoes dimerization and forms tight, long-lived FADH(2)-NAD charge-transfer complexes (CTC) that are proposed to be functionally important. To obtain a deeper insight into structure/function relations and redox mechanism of this vitally important protein, we determined the X-ray structures of oxidized and NADH-reduced forms of naturally folded recombinant murine AIF. Our structures reveal that CTC with the pyridine nucleotide is stabilized by (i) pi-stacking interactions between coplanar nicotinamide, isoalloxazine, and Phe309 rings; (ii) rearrangement of multiple aromatic residues in the C-terminal domain, likely serving as an electron delocalization site; and (iii) an extensive hydrogen-bonding network involving His453, a key residue that undergoes a conformational switch to directly interact with and optimally orient the nicotinamide for charge transfer. Via the His453-containing peptide, redox changes in the active site are transmitted to the surface, promoting AIF dimerization and restricting access to a primary nuclear localization signal through which the apoptogenic form is transported to the nucleus. Structural findings agree with biochemical data and support the hypothesis that both normal and apoptogenic functions of AIF are controlled by NADH.

PubMed: 19447115
DOI: 10.1016/j.jmb.2009.05.013

Experimental method

X-RAY DIFFRACTION (2.95 Å)